Prolongation of Primate Cardiac Allograft Survival by Treatment With Anti-Cd40 Ligand (Cd154) Antibody1

Pierson, Richard N.; Chang, Andrew C.; Blum, Matthew G.; Blair, Kelly; Scott, Margie A.; Atkinson, James B.; Collins, Brendan; Zhang, Jianping; Thomas, David W.; Burkly, Linda C.; Miller, Geraldine G.

doi:10.1097/00007890-199912150-00026

Cited by 75 publications

(58 citation statements)

References 8 publications

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“…Combinations of current immunosuppressive drugs, including steroids, MMF, and tracolimus, seems to counteract the benificial effect of anti-CD40L. The same humanized Ab has been used in a primate model of cardiac transplantation, showing improved survival and less vascular pathology (152).…”

Section: Cd40-cd40l: Role In Transplantationmentioning

confidence: 99%

Immune regulation by CD40-CD40-L interactions - 2; Y2K update

Kooten¹

2000

Front Biosci

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Section: Cd40-cd40l: Role In Transplantationmentioning

confidence: 99%

Immune regulation by CD40-CD40-L interactions - 2; Y2K update

Kooten¹

2000

Front Biosci

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“…We compared expression of four costimulatory pairs during the induction of tolerance and immunity, namely CD40-CD154, OX40-OX40L, RANK-RANKL and PD-1-PD-L1. Exogenous ligation of CD40 has been shown to prevent induction of T cell tolerance [11], while blocking antibodies to CD154 prevent the induction of autoimmunity and prolong allograft survival [12,13], implicating CD40-CD154 signaling in overriding a tolerogenic signal. CD40 ligation induces OX40L expression on DC [14], and exogenous ligation of OX40 has similarly been shown to prevent peptideinduced T cell tolerance [15].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of costimulatory molecule expression by T cells and dendritic cells during the induction of tolerance versus immunity in vivo

Hochweller

Anderton

2005

Eur J Immunol

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Steady-state dendritic cells (DC) present peptide-MHC complexes to T cells in a tolerogenic manner, presumably because of deficient costimulation. However, it is clear that the path to tolerance involves initial T cell activation, suggesting that the deficit may lie in late-acting costimulatory molecules. With this in mind we have investigated the kinetics of expression of several costimulatory pairs on DC and OVA-reactive T cells after i.v. injection of mice with peptide and LPS (immunity), or peptide alone (tolerance). We find that T cells up-regulate CD154, OX40, RANKL and PD-1 whether they are destined for tolerance or immunity, although there are some differences in the levels and length of expression. In contrast, when analyzing DC, we found that up-regulation of CD80, CD86, CD40, RANK and PDL-1 occurred only when peptide was co-administered with LPS. These data give a picture of the T cell looking for costimulatory cues that are not forthcoming when pMHC is presented by steady-state DC, leading to tolerance. However, we did see a strong and rapid up-regulation of RANKL on T cells that occurred specifically when peptide was given in the absence of LPS, suggesting a possible positive signal influencing the decision between tolerance and immunity. IntroductionThe form in which an Ag is administered plays a crucial role in the outcome of the immune response [1]. Ag in aggregated form, or administered with appropriate "danger" signals, such as adjuvant, induces T cell activation leading to a productive immune response. The same Ag administered in soluble, monomeric form (in the absence of "danger"), however, leads to T cell tolerance, as illustrated by the absence of T cell activation when rechallenged with Ag in adjuvant. Administration of soluble peptide Ag via the oral/ mucosal, intravenous (i.v.), intraperitoneal (i.p.), or intranasal (i.n.) routes have all been shown to successfully induce tolerance, and this approach is very effective in preventing several autoimmune models [2]. More recently, these findings have begun to be translated into peptide-based therapeutic trials to treat human autoimmune and allergic disorders, with some encouraging results [3,4]. Relatively little definitive data exist, however, concerning the cellular and molecular processes that lead to T cell tolerance rather than immunity when peptide is administered systemically in soluble form.Most evidence points to a crucial role for the DC in displaying pMHC complexes to T cells after soluble peptide administration. There is no requirement for B cells since peptide-induced tolerance develops in B celldeficient mice [5]. Early data showed that DC, but not B cells, could present efficiently ex vivo when sampled 4 h after i.v. peptide injection [6] An increasing number of costimulatory molecules have been described in recent years, in addition to the classical CD28-CD80/86 interaction. We compared expression of four costimulatory pairs during the induction of tolerance and immunity, namely CD40-CD154, OX40-OX40L, RANK-RANKL and PD-1-PD-...

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“…[1][2][3][4][5][6][7] Although anti-CD40L mAb as a single agent has been shown to facilitate BM and solid organ engraftment in mice, it has been less effective in nonhuman primate transplant models. [8][9][10] Therefore, in these studies, we evaluated the efficacy of the pharmacologic immune suppressive agents, sirolimus, cyclosporine A (CsA), and tacrolimus as single agents and in combination with anti-CD40L mAb for their effects on alloengraftment under a nonmyeloablative-conditioning regime.…”

Section: Introductionmentioning

confidence: 99%

Combined effects of calcineurin inhibitors or sirolimus with anti-CD40L mAb on alloengraftment under nonmyeloablative conditions

Taylor

Lees

Wilson

et al. 2002

Blood

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The immunosuppressive drugs, cyclosporine A (CsA), tacrolimus, or sirolimus, were analyzed as single agents and in combination with anti-CD40L monoclonal antibody (mAb) for their effects on alloengraftment in mice conditioned with minimal total body irradiation (TBI). Whereas anti-CD40L mAb facilitated chimerism, neither sirolimus nor CsA resulted in substantial alloengraftment. However, sirolimus was synergistic with anti-CD40L mAb for inducing donor chimerism. Contrary to expectations, CsA, a T-cell receptor (TCR) signaling inhibitor, did not abrogate anti-CD40L mAb-facilitated engraftment but rather increased engraftment in anti-CD40L mAb-treated mice. Although tacrolimus alone or with anti-CD40L mAb resulted in similar levels of donor chimerism, donor T-cell reconstitution was very low in tacrolimus-treated mice. At 1 week after transplantation, CsA decreased thymic numbers more profoundly than sirolimus or tacrolimus in anti-CD40L mAbtreated recipients. In contrast, only sirolimus resulted in a decrease in host splenic T-cell numbers in anti-CD40L mAbtreated recipients. Importantly, sirolimus and anti-CD40L mAb induced profound donor tolerance with 100% acceptance of donor skin grafts placed early after bone marrow transplantation (BMT). In contrast, anti-CD40L mAb alone or in combination with CsA resulted in 12% or less donor skin graft acceptance early (1 month) and 60% or less later (3 months) after BMT. These data have clinical relevance and indicate that immunosuppressive pharmacologic agents enhance anti-CD40L mAb-facilitated alloengraftment and tolerance induction under nonmyeloablative conditioning. (Blood. 2002; 100:3400-3407)

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Prolongation of Primate Cardiac Allograft Survival by Treatment With Anti-Cd40 Ligand (Cd154) Antibody1

Cited by 75 publications

References 8 publications

Immune regulation by CD40-CD40-L interactions - 2; Y2K update

Immune regulation by CD40-CD40-L interactions - 2; Y2K update

Kinetics of costimulatory molecule expression by T cells and dendritic cells during the induction of tolerance versus immunity in vivo

Combined effects of calcineurin inhibitors or sirolimus with anti-CD40L mAb on alloengraftment under nonmyeloablative conditions

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